Magnetic Resonance Center (CERM), University of Florence, Sesto Fiorentino, (FI), Italy.
Laboratory of Clinical Neurochemistry, Section of Neurology, University of Perugia, Perugia, (PG), Italy.
Mov Disord. 2020 Jan;35(1):34-44. doi: 10.1002/mds.27895. Epub 2019 Nov 15.
The accumulation and misfolding of α-synuclein (α-syn) represent the main pathological hallmark of PD. Overexpression of α-syn and failure of cellular protein degradation systems play a major role in α-syn aggregation. The discovery of PD-associated genes related to the autophagic-lysosomal pathway, such as VPS35, LRRK2, GBA1, SMPD1, GALC, ASAH1, SCARB2, CTSD, CTSB, and GLA, confirms the involvement of cellular clearance systems dysfunction in PD pathogenesis. Of importance, lysosomal enzyme activity is altered both in genetic and sporadic PD. Decreased lysosomal enzymes activities were measured in the same brain regions where α-syn accumulates, suggesting that a crosstalk between α-syn aggregation and autophagic-lysosomal impairment may exist. The understanding of autophagic-lysosomal pathway dysfunctions' role in the pathogenesis and progression of synucleinopathies opened new perspectives for novel possible therapeutic strategies. In this article, the evidences and mechanisms of the reciprocal relation between autophagic-lysosomal pathway impairment and misfolded α-syn aggregation and propagation are reviewed, together with the most promising compounds targeting autophagic-lysosomal pathway restoration as a disease-modifying strategy for PD treatment. © 2019 International Parkinson and Movement Disorder Society.
α-突触核蛋白（α-syn）的积累和错误折叠是 PD 的主要病理标志。α-syn 的过表达和细胞蛋白降解系统的失败在 α-syn 聚集中起主要作用。与自噬溶酶体途径相关的 PD 相关基因的发现，如 VPS35、LRRK2、GBA1、SMPD1、GALC、ASAH1、SCARB2、CTSD、CTSB 和 GLA，证实了细胞清除系统功能障碍在 PD 发病机制中的作用。重要的是，遗传和散发性 PD 中溶酶体酶活性均发生改变。在α-syn 积累的相同脑区测量到溶酶体酶活性降低，表明α-syn 聚集和自噬溶酶体损伤之间可能存在相互作用。自噬溶酶体途径功能障碍在突触核蛋白病发病机制和进展中的作用的理解为新的可能治疗策略开辟了新的前景。本文综述了自噬溶酶体途径损伤与错误折叠的α-syn 聚集和传播之间的相互关系的证据和机制，以及最有前途的靶向自噬溶酶体途径恢复的化合物作为 PD 治疗的疾病修饰策略。
